Synthesis of Isocoumarin Derivatives via the Copper-Catalyzed

Chia-Yu Huang , Veerababurao Kavala , Chun-Wei Kuo , Ashok Konala , Tang-Hao Yang , and .... Yan He , Xinying Zhang , Nana Shen , and Xuesen Fan...
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Synthesis of Isocoumarin Derivatives via the Copper-Catalyzed Tandem Sequential Cyclization of 2- Halo-N-phenyl Benzamides and Acyclic 1,3-Diketones Veerababurao Kavala, Cheng-Chuan Wang, Deepak Kumar Barange, Chun-Wei Kuo, Po-Min Lei, and Ching-Fa Yao* Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road, Taipei, Taiwan 116, R.O.C. S Supporting Information *

ABSTRACT: A facile and rapid synthesis of isocoumarin derivatives using a copper-catalyzed tandem C−C/C−O coupling strategy from readily available substrates is described. The reactions of a wide range of 2-iodo-N-phenyl benzamides and acyclic diketones as starting materials were investigated.

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INTRODUCTION Copper-catalyzed tandem sequential cyclization reactions are powerful tools for the construction of a wide variety of heterocyclic frame works.1 A wide range of heterocycles including indoles, benzofurans, quinolines, isoqunolines, quinazalines, quinazolones, and many more heterocycles have been synthesized using this approach.2 We also recently reported on a copper-catalyzed tandem cyclization leading to the synthesis of triazole fused sultum derivatives3 In a continuation to our interest in copper-catalyzed tandem cyclization reactions, we wish to investigate the synthesis of isoquinolinone4 derivatives using 2-halo-N-alkyl/aryl-benzamides and 1,3-dicarbonyl as the starting compounds. In fact, Wang et al. reported on the synthesis of isoquinolinone derivatives from the 2-halobenzamides and with various ketoesters (Scheme 1).5 They did not, however, investigate the possibility of using 1,3-diketones as coupling partners with N-substituted-2-halobenzamides.

was completely consumed, and two products were produced. Both products were isolated and characterized by 1H NMR, 13C NMR, and HRMS. From the analytical data, the first product was determined to be 3-methylisocoumarin, and the second was acetanilide. The structure of the 3-methylisocoumarin product was further confirmed by single crystal X-ray analysis (Supporting Information). No trace of isoquinolinone derivative was observed in this reaction. This interesting result prompted us to investigate the reaction in more detail. Isocoumarins are an important class of heterocyclic scaffolds that exhibit a wide range of biological activities.6 In addition, isocoumarin derivatives are useful precursors for the synthesis of various natural products and isoquinoline derivatives.7 A plethora of methods are available for the construction of isocoumarin rings from various sources.8 However, most of the reported procedures have drawbacks, which include the use of expensive catalysts such as palladium or rhodium, the need for complex starting materials, and drastic conditions. Therefore, an easy and handy method for the synthesis of isocoumarin derivatives would be highly desirable, considering the above drawbacks. Given this situation, we now report a new methodology for the rapid synthesis of isocoumarin derivatives by a copper-catalyzed one-pot sequential cyclization. While our manuscript was being prepared, we found two papers based on a similar concept for the synthesis of isocoumarin derivatives using 2-iodobenzoic acids9 and methyl-2-iodobenzoates10 as starting compounds. However, the conditions described in these protocols required quite long reaction times, and when substrates containing electron-withdrawing groups were used, the product yields were low. The reaction is presumably initiated with the reaction of copper iodide and acetylacetone to produce a copper(I) complex, and the oxidative addition of 2-iodo-N-phenyl-

Scheme 1. Approach by Wang et al. to the Synthesis of Isoquinolin-1(2H)-one Derivatives

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RESULTS AND DISCUSSION To pursue our objective, we used 2-iodo- N-phenyl-benzamide and acetylacetone as model substrates. The reaction of 2-iodoN-phenyl-benzamide and acetylacetone was conducted in the presence copper(I) iodide (10 mol %) and cesium carbonate in DMSO at 100 °C. After a 10 min reaction, the starting amide © 2012 American Chemical Society

Received: March 9, 2012 Published: April 18, 2012 5022

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benzamide to this copper(I) complex results in the formation the Cu(III) intermediate (II). The base-mediated abstraction of the amidic proton from the intermediate (II) followed by the intramolecular nucleophilic addition of the amide nitrogen to one of the carbonyl groups of intermediate (III) produces the intermediate (IV). Since this intermediate (IV) is a charged species, it is unstable. Hence, it undergoes a C−C bond cleavage to furnish intermediate (V), which is further converted to intermediate (VI) via reductive elimination. The attack of acetylacetone on intermediate (VI) results in the regeneration of the copper catalyst and the formation of intermediate (VII). Intermediate (VII) then loses an acetanilide (4a) molecule to produce the isocoumarin derivative 3a (Scheme 2). This

Table 1. Reactions of Various 2-Benzoic Acid Derivatives with Acetylacetone

Scheme 2. Plausible Mechanistic Pathway

a

Reaction conditions: nitrogen atmosphere, 1 (0.5 mmol), 2a (1 mmol), Cs2CO3 (1 mmol), CuI (0.05 mmol), DMSO (3 mL). bNMR yield with CH2Br2 as internal standard.

attributed to the stronger ortho effect of N-phenylamides.12 It is interesting to note that the reactions of methyl-2iodobenzoate and N,N-diethyl-2-iodobenzamide failed to give the expected products. However, Fan et al.10 have obtained moderate yield of the product with methyl-2-bromobenzoate with the same catalyst in the presence of K2CO3 as base and DMF as solvent. The reason for this failure may be due to the absence of the nucleophilic oxygen or a nitrogen site in both entry 5 and entry 6. From all of the experiments described in Table 1, it is quite clear that 2-iodo-N-phenyl-benzamide derivatives are superior for the generation of isocoumarin derivatives. Hence, we then used a variety of substituted 2-iodoN-phenyl-benzamide derivatives for the synthesis of a structurally diverse series of isocoumarin derivatives. Encouraged by these initial observations, we first focused our attention on optimizing the reaction conditions. In this regard, we examined various solvents. The findings indicated that the reaction proceeded well in polar aprotic solvents such as DMF and DMSO, and moderate yields were obtained when acetonitrile was used. The poor yields were obtained when a nonpolar solvent, such as toluene, was used. The next screened various copper sources. The reaction was equally efficient when copper salts such as CuCl, CuBr, and CuI were used. We also tested various inorganic bases in the reaction. Both cesium

reaction mechanism is very similar to the mechanism proposed by Lei and co-workers for the reaction of aryl halides with acetyl acetone.11 The difference here is the internal nucleophile (amidic nitrogen) attack on one of the carbonyl carbons of the Cu(III) complex, whereas in Lei’s proposed mechanism the attack involves an external nucleophile (H2O). To determine if other 2-iodobenzoic acid derivatives, such as 2-iodobenzoic acid, methyl-2-iodobenzoate, and N-alkyl-2iodobenzamide, could be used in this reaction, we examined the reaction of all of these derivatives with acetylacetone in the presence of the copper catalyst (CuI) and cesium carbonate in DMSO at 100 °C. The results were summarized in Table 1. As can be seen from the Table 1, when 2-iodo-benzoic acid was used in the reaction, the desired product was produced in moderate yield. In this case, however, the reaction time needed to be extended, compared with the use of amide derivatives such as 2-iodo-N-methyl-benzamide and N-benzyl-2-iodobenzamide. It should also be noted that the reaction of 2-iodo-Nphenyl-benzamide resulted in the production of high yields of the expected isocoumarin derivative within 10 min. When the reaction was performed with 2-iodo-N-(4-nitrophenyl)benzamide under the present reaction conditions, the reaction completed in 10 min but yield of the product was 85%. The higher reactivity of 2-iodo-N-phenylbenzamides may be 5023

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carbonate and potassium carbonate were found to be more efficient for this reaction (Table 2).

Table 3. Scope of the Reaction with Respect to Various 2Iodo-N-phenyl-benzamides

Table 2. Screening for Reaction Conditions

entrya

catalyst

base

solvent

temp (°C)

time (h)

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13

CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuCl CuBr

Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 K2CO3 Na2CO3 K3PO4 Cs2CO3 Cs2CO3

toluene dioxane MeCN DMF DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO

90 100 60 100 60 80 100 100 100 100 100 100 100

40 12 19 0.5 7 2.5 0.16 0.5 1.5 3 49 0.5 0.5

50 26 95 81 85 93 98 85 92 79 16 90 87

a Reaction conditions:nitrogen atmosphere, 1a (0.5 mmol), 2a (1 mmol), Cs2CO3 (1 mmol), CuI (0.05 mmol), solvent (3 mL). bNMR yields with CH2Br2 as internal standard.

With the optimal conditions in hand, the scope of the tandem sequential cyclization was then explored. The reaction of a variety of 2-iodo-N-phenyl-substituted benzamide derivatives with acetylacetone was initially examined, and the results are summarized in Table 3. Reactions of 2-iodo-N-phenylsubstituted benzamide derivatives containing electron-withdrawing or electron-donating groups with acetylacetone were performed under the optimized reaction conditions, and the corresponding isocoumarin derivatives were produced in good to excellent yields. It is noteworthy that when substrates that contained electron-releasing groups were used, the reaction required a longer time compared to reactions of substrates possessing electron-withdrawing groups. The reaction is very fast in the case of substrates with electron-withdrawing groups. In particular, substrates containing nitro and dibromo functional groups react rapidly to produce the corresponding product. It is important to note that products containing electron-withdrawing groups were very unstable under the reaction conditions used, and it was necessary to quench the reaction immediately after completion of the reaction. In the case of substrates having nitro and fluoro groups, the reaction was very rapid and the product also decomposed rapidly in the reaction medium. Next, the scope of this reaction was extended to various 1,3dicarbonyl compounds. When an unsymmetrical diketone such as 1-phenylbutane-1,3-dione was used as the coupling partner in the reaction with 1a, we observed the formation of two isomeric products in which 3-phenylisocoumarin (56%) was the major product and 3-methylisocoumarin the minor product (10%). Reactions with symmetrical substituted diphenylpropane-1,3-dione derivatives gave a single product in moderate yields. Under the present reaction conditions, several unidentified products were produced when 3-methylpentane-

a

Reaction conditions: nitrogen atmosphere, 1 (1 mmol), 2a (2 mmol), Cs2CO3 (2 mmol), CuI (0.1 mmol), DMSO (3 mL). bIsolated yields. c Reaction performed at 80 °C.

2,4-dione and ethylacetoacetate were employed as substrates (Table 4). To further demonstrate the generality of our methodology, we utilized 2-bromo-N-phenyl-benzamide and 2-chloro-Nphenyl-benzamide as substrates. To our delight, both substrates gave the corresponding product within very short time (Scheme 3). This reaction trend is also consistent with the stronger ortho effect of N-phenylamides.13 Pyranoquinoline is one of the prominent structural motifs found in alkaloids extracted from rutaceae plants.14 Derivatives of pyranoquinoline compounds are known to exhibit a wide range of pharmacological and biological activities and can have antiallergic, anticoagulant, coronary constricting, and antihistamic effects.15 Considering the importance of the pyranoquino5024

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Table 4. Scope of the Reaction with Respect to Various 1,3-Diketones

a

Reaction conditions: nitrogen atmosphere, 1 (1 mmol), 2 (1.2 mmol), Cs2CO3 (2 mmol), CuI (0.1 mmol), DMSO (3 mL). bIsolated yields.

Scheme 3. Reaction of Chloro and Bromo Benzamides with Acetylacetone

line derivatives, we attempted to synthesize these derivatives using the present method. Starting materials such as 2-chloroN-phenylquinoline-3-carboxamide derivatives were synthesized in four steps, starting from aniline, by following established procedures.16 These 2-chloro-N-phenylquinoline-3-carboxamide derivatives were treated with acetylacetone under the optimized reaction conditions, and pyarnoquinolinone derivatives were produced in good yields (Table 5). As can be seen in

Table 5, it is important to note that all of the 2-chloro-Nphenylquinoline-3-carboxamide derivatives participated in the reaction with equal ease to produce the corresponding pyranoquinolinone derivatives. It should also be noted that the present methodology can also be used in the synthesis of benzopyranoquinolinone derivatives. The structure of the newly synthesized pyranoquinolinone derivatives were con5025

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Table 5. Synthesis of Pyranoquinolinone Derivatives

a

Reaction conditions: nitrogen atmosphere, 1 (1 mmol), 2a (2 mmol), Cs2CO3 (2 mmol), CuI (0.1 mmol), DMSO (3 mL). bIsolated yield.

firmed by the single crystal X-ray analysis of a representative sample, namely, compound 3s (Figure 1).

Figure 2. Single crystal structure of compound 6a.

variety of different electronic properties and various 1,3diketones could be successfully used to access structurally diverse isocoumarin derivatives in good to excellent yields. In addition, this methodology can also be utilized for the synthesis of various pyranoquinolinone derivatives, which are important constituents in many pharmaceutically active substances. Interestingly, the reaction involving 1,3-cyclohexadione gave an isoquinolinone derivative. Further investigations of the scope of this reaction are currently underway in our laboratory.

Figure 1. Single crystal structure of compound 3s.

Finally, we carried out the reaction of 2-iodo-N-phenylbenzamide with a cyclic diketone 1,3-cyclohexadione using the present reaction conditions (Scheme 4). To our delight, an isoquinolinone derivative was produced (Figure 2). This outcome is very different from reactions involving acyclic ketones. In summary we report herein on the efficient rapid synthesis of isocoumarin derivatives by employing copper-catalyzed tandem C−C/C−O coupling transformation as the key step. A remarkable number of 2-iodo-N-phenyl-benzamides with a

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EXPERIMENTAL SECTION

All chemicals were purchased from various sources and used directly without further purification. Analytical thin-layer chromatography was performed using silica gel 60F glass plates and gel 60 (230−400 mesh) was used in flash chromatography separations. NMR spectra were recorded in CDCl3 with tetramethylsilane as the internal standard for 1 H NMR (400 MHz) and CDCl3 solvent as the internal standard for 13 C NMR (100 MHz), and coupling constants are expressed in hertz. HRMS spectra were recorded using ESI-TOF or EI+ mode. Melting points were recorded using an electrothermal capillary melting point apparatus and are uncorrected. General Procedure. A 25 mL round-bottom flask was charged with a magnetic stirrer and 3 mL of DMSO. Substituted N-pheny-2halobenzamide (1 mmol), 1,3-diketone (1.2 mmol), copper(I) iodide (10 mol %), and cesium carbonate (2 mmol) were then added to the

Scheme 4. Reaction of 2-Iodo-N-phenyl-benzamide with 1,3Cyclohexadione

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flask. The reaction solution was stirred at 100 °C under N2 until the reaction was complete as evidenced by TLC. After completion of the reaction, the resulting solution was transferred to a beaker containing crushed ice, and the resulting solid was isolated on a filter. In most cases, the isolated solid contained only the isocoumarin derivative (3) and the amide remained in the solution (4). In a very few cases the solid was a mixture of the products. In such cases, the crude product was purified by column chromatography (ethylacetate/hexane) on silica gel. Spectral Data. 3-Methyl-1H-isochromen-1-one (3a). Pale yellow solid; 144.2 mg (90%); mp 70−72 °C. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 7.96 Hz, 1H), 7.66 (td, J = 7.60, 1.13 Hz, 1H), 7.46−7.42 (m, 1H), 7.33 (d, J = 7.84 Hz, 1H), 6.25 (s, 1H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.1, 154.7, 137.8, 134.8, 129.6, 127.6, 125.0, 120.0, 103.6, 19.7; MS (ESI) m/z (relative intensity) 161 (M + H, 100), 143 (18). HRMS (ESI) m/z calcd for C10H8O2 (M + H) 161.0603, found 161.0603. 3,7-Dimethyl-1H-isochromen-1-one (3b). White solid; 128.9 mg (74%); mp 122−124 °C. 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.48 (d, J = 8 Hz, 1H), 7.23 (d, J = 8 Hz, 1H), 6.22 (s, 1H), 2.44 (s, 3H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.3, 153.8, 137.8, 136.2, 135.3, 129.3, 124.9, 119.9, 103.5, 21.4, 19.7; MS (ESI) m/z (relative intensity) 175 (M + H, 100), 147 (2). HRMS (ESI) m/z calcd for C11H10O2 (M + H) 175.0759, found 175.0747. 7-Methoxy-3-methyl-1H-isochromen-1-one (3c). White solid; 165.5 mg (87%); mp 96−98 °C. 1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.27 (d, J = 1.08 Hz, 2H), 6.22 (s, 1H), 3.89 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.2, 159.1, 152.4, 131.4, 126.5, 124.5, 121.0, 109.9, 103.2, 55.7, 19.5; MS (ESI) m/z (relative intensity) 191 (M + H, 100), 173 (4), 145 (2). HRMS (ESI) m/z calcd for C11H10O3 (M + H) 191.0708, found 191.0705. 6,7-Dimethoxy-3-methyl-1H-isochromen-1-one (3d). Blue solid; 187.3 mg (85%); mp 126−128 °C. 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 6.70 (s, 1H), 6.18 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.1, 155.3, 153.6, 149.4, 133.5, 113.1, 109.6, 105.7, 103.3, 56.4, 56.3, 19.7; MS (EI) m/z (relative intensity) 220 (M+, 100), 171 (68), 170 (64), 149 (16), 115 (6). HRMS (EI) m/z calcd for C12H12O4 (M+) 220.0736, found 220.0739. 7,8-Dimethoxy-3-methyl-1H-isochromen-1-one (3e). Pale yellow solid; 154.2 mg (72%); mp 93−95 °C. 1H NMR (400 MHz, CDCl3) δ 7.29 (d,, J = 9.2 Hz, 1H), 7. 02 (d,, J = 9.2 Hz, 1H), 6.11(s, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 2.20 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.7, 152.6, 152.3, 151.2, 132.5, 120.7, 120.4, 114.6, 103.2, 61.7, 56.8, 19.5; MS (EI) m/z (relative intensity) 220 (M+, 100), 205(74), 191 (46), 147 (16). HRMS (EI) m/z calcd for C12H12O4 (M+) 220.0736, found 220.0740. 7-Methyl-5H-[1,3]dioxolo[4,5-g]isochromen-5-one (3f). Pale pink solid; 147.4 mg (72%); mp 187−189 °C. 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 6.70 (s, 1H), 6.14 (s, 1H), 6.07 (s, 2H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.7, 153.8, 153.7, 148.0, 135.5, 114.6, 107.5, 103.7, 103.6, 102.2, 19.6; MS (EI) m/z (relative intensity) 204 (M+, 44), 162 (27), 133 (32). HRMS (EI) m/z calcd for C11H8O4 (M+) 204.0423, found 204.0422. 6-Fluoro-3-methyl-1H-isochromen-1-one (3g). Colorless solid; 123.2 mg (69%); mp 96−98 °C. 1H NMR (400 MHz, CDCl3) δ 8.25−8.22 (m, 1H), 7.11 (td, J = 8.62, 2.33 Hz, 1H), 6.96 (dd, J = 8.92, 2.30 Hz, 1H), 6.20 (s, 1H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.8 (d, JC−F = 255 Hz), 162.1, 156.2, 140.5 (d, JC−F = 10 Hz), 133.0 (d, JC−F = 11 Hz), 116.6, 115.9 (d, JC−F = 23 Hz), 110.6 (d, JC−F = 22 Hz), 103.2 (d, JC−F = 3 Hz), 19.8; MS (EI) m/z (relative intensity) 178 (M+, 100), 136 (23), 107 (23). HRMS (EI) m/z calcd for C10H7FO2 (M+) 178.0430, found 178.0435. 6-Chloro-3-methyl-1H-isochromen-1-one (3h). White solid; 134.3 mg (70%); mp 152−154 °C. 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.44 Hz, 1H), 7.39 (dd, J = 8.52, 1.98 Hz, 1H), 7.32 (d, J = 1.88 Hz, 1H), 6.18 (s, 1H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.2, 156.2, 141.5, 139.1, 131.3, 128.2, 124.5, 118.4, 102.8, 19.9; MS (ESI) m/z (relative intensity) 195 (M + H, 26), 172 (21),

150 (100), 161 (12), 136 (6). HRMS (ESI) m/z calcd for C10H7ClO2 (M + H) 195.0213, found 195.0199. 3-Methyl-7-nitro-1H-isochromen-1-one (3i). Yellow solid; 156.6 mg (76%); mp 176−178 °C. 1H NMR (400 MHz, CDCl3) δ 9.08 (d, J = 2.12 Hz, 1H), 8.47 (dd, J = 8.72, 2.36 Hz, 1H), 7.49 (d, J = 8.64 Hz, 1H), 6.38 (s, 1H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.1, 159.0, 146.8, 142.7, 129.1, 126.4, 125.8, 120.4, 103.1, 20.1; MS (EI) m/z (relative intensity) 205 (M+, 100), 175 (26), 159 (16), 103 (13). HRMS (EI) m/z calcd for C10H7NO4 (M+) 205.0375, found 205.0373. 7-Chloro-3-methyl-1H-isochromen-1-one (3j). Colorless solid; 161.8 mg (83%); mp 148−150 °C. 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 1.88 Hz, 1H), 7.61 (dd, J = 8.40, 2.14 Hz, 1H), 7.28 (d, J = 8.40 Hz, 1H), 6.23 (s, 1H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.9, 155.1, 136.1, 135.2, 133.3, 129.0, 126.6, 121.2, 103.0, 19.8; MS (EI) m/z (relative intensity) 194 (M+, 100), 152 (22), 123 (17), 102 (3). HRMS (EI) m/z calcd for C10H7ClO2 (M+) 194.0135, found 194.0133. 5,7-Dibromo-3-methyl-1H-isochromen-1-one (3k). Pale yellow solid; 270.7 mg (85%); mp 148−150 °C. 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 1.68 Hz, 1H), 8.02 (d, J = 2.00 Hz, 1H), 6.57 (s, 1H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.8, 156.5, 140.7, 136.0, 131.6, 122.4, 120.7, 120.3, 102.0, 20.2; MS (EI) m/z (relative intensity) 320 (M+ + 4, 54), 318 (M+ + 2, 100), 315 (M+, 44), 275 (11), 239 (13), 237 (12), 170 (34), 102 (7). HRMS (EI) m/z calcd for C10H6Br2O2 (M+) 315.8735, found 315.8737. 2-Methyl-4H-benzo[f ]isochromen-4-one (3l). Colorless solid; 197.8 mg (94%); mp 166−168 °C. 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.36 Hz, 1H), 8.20 (d, J = 8.72 Hz, 1H), 7.92 (d, J = 8.44 Hz, 1H), 7.83 (d, J = 8.72 Hz, 1H), 7.72−7.64 (m, 2H), 7.04 (s, 1H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.4, 156.3, 137.0, 136.1, 129.4, 128.9, 127.9, 127.4, 127.2, 124.2, 124.1, 116.8, 99.5, 20.3; MS (ESI) m/z (relative intensity) 211 (M + H, 100), 195 (7), 122 (3). HRMS (ESI) m/z calcd for C14H10O2 (M + H) 211.0759, found 211.0754. 3-Phenyl-1H-isochromen-1-one (3m). Pale yellow solid; 142.5 mg (64%); mp 89−91 °C; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.20 Hz, 1H), 7.90−7.88 (m, 2H), 7.72 (td, J = 7.60, 0.96 Hz, 1H), 7.52−7.43 (m, 5H), 6.96 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 162.3, 153.7, 137.6, 134.9, 132.0, 130.0, 129.7, 128.9, 128.2, 126.1, 125.3, 120.6, 101.9; MS (ESI) m/z (relative intensity) 223 (M + H, 100), 201 (10), 195 (5). HRMS (ESI) m/z calcd for C15H10O2 (M + H) 223.0759, found 223.0734. 3-(p-Tolyl)-1H-isochromen-1-one (3n). White solid; 153.9 mg (65%); mp 118−120 °C; 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.04 Hz, 1H), 7.78 (d, J = 8.08 Hz, 2H), 7.70 (t, J = 7.62 Hz, 1H), 7.50−7.46 (m, 2H), 7.27 (d, J = 8.08 Hz, 2H), 6.91 (s, 1H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.5, 154.0, 140.4, 137.9, 134.9, 129.8, 129.7, 129.4, 128.0, 126.0, 125.3, 120.6, 101.2, 21.5; MS (EI) m/z (relative intensity) 236 (M+, 100), 208 (74), 165 (22), 152 (3), 119 (4). HRMS (EI) m/z calcd for C16H12O2 (M+) 236.0837, found 236.0838. 3-(4-Methoxyphenyl)-1H-isochromen-1-one (3o). White solid; 201.8 mg (80%); mp 120−122 °C; 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 7.36 Hz, 1H), 7.83 (d, J = 9.00 Hz, 2H), 7.72−7.67 (m, 1H), 7.48−7.44 (m, 2H), 6.98 (d, J = 8.88 Hz, 2H), 6.84 (s, 1H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.7, 161.3, 153.9, 138.1, 135.0, 129.8, 127.8, 127.0, 125.9, 124.7, 120.3, 114.4, 100.4, 55.6; MS (EI) m/z (relative intensity) 252 (M+, 100), 224 (60), 181 (17), 152 (9), 112 (5). HRMS (EI) m/z calcd for C16H12O3 (M+) 252.0786, found 252.0780. 6-Chloro-3-phenyl-1H-isochromen-1-one (3p). White solid; 175.2 mg (68%); mp 212−214 °C; 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.44 Hz, 1H), 7.88−7.86 (m, 2H), 7.48−7.43 (m, 5H), 6.88(s, 1H); 13C NMR (100 MHz, CDCl3) δ 161.7, 155.2, 141.7, 139.1, 131.8, 131.5, 130.6, 129.1, 128.8, 125.6, 119.0, 101.0; MS (EI) m/z (relative intensity) 256 (M+, 60), 211 (84), 193 (15), 165 (21), 119 (100). HRMS (EI) m/z calcd for C15H9ClO2 (M+) 256.0291, found 256.0297. 5027

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The Journal of Organic Chemistry

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7.84 Hz, 2H), 7.16−7.12 (m, 1H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.9, 142.5, 138.2, 132.3, 129.5, 129.2, 127.2, 124.6, 120.4, 21.6; MS (EI) m/z (relative intensity) 211 (M+, 65), 167 (1), 119 (100); HRMS (EI) m/z calcd for C14H13NO (M+) 211.0997, found 211.0994.

5,7-Dibromo-3-(p-tolyl)-1H-isochromen-1-one (3q). Greenish yellow solid; 275.8 mg (70%); mp 216−218 °C. 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.06 (d, J = 1.84 Hz, 1H), 7.80 (d, J = 8.28 Hz, 2H), 7.29 (d, J = 8.24 Hz, 2H), 7.19 (s, 1H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.5, 155.5, 141.4, 141.0, 136.3, 131.9, 129.9, 128.8, 125.7, 122.9, 121.3, 121.0, 99.4, 21.7; MS (EI) m/z (relative intensity) 396 (M+ + 4, 58), 394 (M+ + 2, 100), 391 (M+, 58), 366 (55), 178 (10), 119 (12). HRMS (EI) m/z calcd for C16H10Br2O2 (M+) 391.9048, found 391.9054. 6,8-Dichloro-3-methyl-1H-isochromen-1-one (3r). Colorless solid; 158.7 mg (70%); mp 163−165 °C. 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 1.72 Hz, 1H), 7.20 (d, J = 1.68 Hz, 1H), 6.14 (s, 1H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.8, 157.0, 141.6, 138.4, 130.4, 123.6, 115.6, 102.9, 19.7; MS (EI) m/z (relative intensity) 228 (M+, 100), 213 (38), 157 (30). HRMS (EI) m/z calcd for C10H6Cl2O2 (M+) 227.9745, found 227.9743. 3-Methyl-1H-pyrano[4,3-b]quinolin-1-one (3s). Yellow solid; 143.9 mg (68%); mp 198−200 °C; 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.09 (d, J = 8.96 Hz, 1H), 7.98 (d, J = 8.20 Hz, 1H), 7.90−7.85 (m, 1H), 7.61−7.57 (m, 1H), 6.61 (s, 1H), 2.38 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 162.6, 158.6, 152.7, 151.6, 140.5, 133.4, 129.6, 129.1, 127.0, 126.9, 115.1, 106.0, 20.2; HRMS (ESI) m/z calcd for C13H9NO2 (M + H) 212.0711, found 212.0703; MS (ESI) m/z (relative intensity) 212 (M + H, 100), 202 (20), 184 (55), 156 (15). 8-Methoxy-3-methyl-1H-pyrano[4,3-b]quinolin-1-one (3t). Yellow solid; 161.6 mg (67%); mp 232−234 °C. 1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 7.98 (d, J = 9.32 Hz, 1H), 7.52 (dd, J = 9.28, 2.66 Hz, 1H), 7.17 (d, J = 2.56 Hz, 1H), 6.57 (s, 1H), 3.96 (s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.0, 158.1, 157.5, 150.8, 148.2, 138.5, 130.5, 128.1, 127.2, 115.3, 106.0, 105.8, 55.9, 20.2; HRMS (EI) m/z calcd for C14H11NO3 (M+) 241.0739, found 241.0744; MS (EI) m/z (relative intensity) 241 (M+, 100), 226 (35), 198 (22), 170 (12), 119 (22). 3,6-Dimethyl-1H-pyrano[4,3-b]quinolin-1-one (3u). Pale brown solid; 168.6 mg (75%); mp 188−190 °C. 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 7.80 (d, J = 8.24 Hz, 1H), 7.70 (d, J = 6.6 Hz, 1H), 7.46 (t, J = 7.50 Hz, 1H), 6.66 (s, 1H), 2.81 (s, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.0, 158.0, 151.7, 150.8, 140.5, 137.3, 133.2, 127.5, 126.9, 126.6, 114.8, 106.6, 20.2, 18.2; HRMS (EI) m/z calcd for C14H11NO2 (M+) 225.0790, found 225.0793; MS (EI) m/z (relative intensity) 225 (M+, 100), 182 (11), 154 (13), 127 (3). 10-Methyl-8H-benzo[h]pyrano[4,3-b]quinolin-8-one (3v). Yellow solid; 156.7 mg (60%); mp 262−264 °C. 1H NMR (400 MHz, CDCl3) δ 9.34−9.32 (m, 1H), 9.00 (s, 1H), 7.92−7.90 (m, 1H), 7.81−7.73 (m, 4H), 6.76 (s, 1H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.1, 158.4, 152.4, 151.3, 138.7, 135.3, 130.9, 130.2, 128.4, 128.2, 127.6, 125.9, 125.7, 125.5, 115.1, 106.6, 20.2; HRMS (EI) m/z calcd for C17H11NO2 (M+) 261.0790, found 261.0795; MS (EI) m/z (relative intensity) 261 (M+, 100), 246 (10), 219 (7), 190 (17), 171 (7), 163 (3), 127(3), 111 (3). 5-Phenyl-3,4-dihydrophenanthridine-1,6(2H,5H)-dione (6a). Pale yellow solid; 130.3 mg (45%); mp 187−189 °C. 1H NMR (400 MHz, CDCl3) δ 9.27 (d, J = 8.52 Hz, 1H), 8.40 (dd, J = 7.96, 1.34 Hz, 1H), 7.79−7.74 (m, 1H), 7.59−7.49 (m, 4H), 2.62 (t, J = 6.66 Hz, 2H), 2.51 (t, J = 6.18 Hz, 2H), 2.05−1.99 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 196.9, 162.9, 154.3, 138.3, 134.4, 133.9, 130.1, 129.3, 128.4, 127.9, 127.2, 126.5, 124.8, 111.6, 39.8, 30.5, 21.2; HRMS (ESI) m/z calcd for C19H15NO2 (M + H) 290.1181, found 290.1184; MS (ESI) m/z (relative intensity) 290 (M + H, 100), 288 (4). N-Phenylacetamide(4a). Pale yellow solid; mp 114−116 °C. 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.96 Hz, 2H), 7.31 (t, J = 7.66 Hz, 3H), 7.10 (t, J = 7.34 Hz, 1H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.8, 138.1, 129.1, 124.4, 120.2, 24.6; HRMS (ESI) m/z calcd for C8H9NO (M + H) 136.0762, found 136.0746; MS (ESI) m/z (relative intensity) 136 (M + H, 100). 4-Methyl-N-phenylbenzamide(4b). Greenish yellow solid; mp 142−144 °C. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.12 Hz, 3H), 7.63 (d, J = 7.64 Hz, 2H), 7.37 (t, J = 7.94 Hz, 2H), 7.28 (d, J =

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ASSOCIATED CONTENT

S Supporting Information *

Crystallographic data of compound 3a, 3l, 3q, and 6a in CIF format and copies of 1H and 13C NMR spectra of all the compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support for this work by the National Science Council of the Republic of China (NSC 100-2113-M-003-008-MY3) and National Taiwan Normal University (99T3030-2, 99-D, 100-D-06) is gratefully acknowledged.

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REFERENCES

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The Journal of Organic Chemistry

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dx.doi.org/10.1021/jo300501j | J. Org. Chem. 2012, 77, 5022−5029